Insecticidal and fungicidal usage of beta-arylamino cinnamoyl compounds



United States Patent M 3,355,351 INSECTICIDAL AND FUNGICIDAL USAGE 0F ,6-

ARYLAMINO CINNAMOYL COMPOUNDS Kenneth Wayne Ratts, Creve Coeur, Mo., assignor to Monsanto Company, St. Louis, Mo., a corporation of Delaware No Drawing. Original application June 28, 1965, Ser. No. 467,722. Divided and this application Sept. 29, 1965, Ser. No. 491,425

7 Claims. (Cl. 16730) ABSTRACT OF THE DISCLOSURE This invention relates to the insecticidal and fungicidal usage of alkyl B-arylamino-cinnamates and N-aliphatic or N-N-dialiphatic B-arylamino-cinnamides.

This application is a division of copending application Serial No. 467,722, filed June 28, 1965.

The sulfonium halides which are precursors for the fungicidal and insecticidal agents of this invention can be represented by the general formula wherein X is halogen of atomic weight in the range of 35 to 127 (i.e. chlorine, bromine or iodine), wherein R" and R' are like or unlike lower alkyl (i.e. methyl, ethyl, propyl, butyl, and the various isomeric forms thereof containing up to and including four carbon atoms), and wherein A is either lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, and the various isomeric forms thereof containing up to and including four carbon atoms) or, and preferably,

wherein R is lower alkyl or lower alkenyl or lower alkoxyalkyl (e.g. methyl, ethyl, propyl, butyl, allyl, butenyl, methoxyethyl, ethoxyethyl, methoxypropyl, and the various isomeric forms thereof containing up to and including four carbon atoms) and wherein R is hydrogen or lower alkyl or lower alkenyl or lower alkoxyalkyl (e.g. methyl, ethyl, propyl, butyl, allyl, butenyl, methoxyethyl, ethoxyethyl, methoxypropyl, and the various isomeric forms thereof containing up to and including four carbon atoms). It is preferred that X be chlorine, that R" and R" be C alkyl (i.e. methyl or ethyl) and that both R and R be either like lower n-alkyl or like lower n-alkenyl. This preferred group is particular- Iy useful as foliage fungicides, as for example controlling Venturia inaequalis (apple scab).

The sulfonium chloride and bromide precursors are prepared by reacting a sulfide of the formula R"S"', wherein R" and R'" have the aforedescribed significance, with a substantially equimolecular proportion of an 0:.- haloaceto compound of the formula wherein Z is chlorine or bromine and wherein A has the aforedescribed significance, in a fluid system (i.e. a reaction temperature above the freezing point of the system up to and including the reflux temperature of the system or the decomposition temperature of the sulfonium halide). Where and when desired an inert organic solvent can be used, e.g. benzene, toluene, Xylene, hexane, heptane, octane, and the like. The sulfonium iodides are prepared by mixing potassium iodide with a concentrated aqueous solution of the appropriate sul- 3,355,351 Patented Nov. 28, 1967 fonium chloride in substantially equimolecular proportions at room temperature, the sulfonium iodide product being less water-soluble than the sulfonium chloride reactant precipitates out and is recovered by simple filtration. Exemplary of the sulfide reactants are dimethyl sulfide, diethyl sulfide, di-n-propyl sulfide, diisopropyl sulfide, di-n-butyl sulfide, methylethyl sulfide, ethylisopropyl sulfide, butylmethyl sulfide, and the like. Exemplary of the a-haloaceto compound reactants are N,N-dimethyl-u-chloroacetamide, N,N diethyl a chloroacetamide, N,N diisopropyl a chloroacetarnide, N methyl oz chloroacetamide, N ethyl-u-chloroacetamide, N allyl on chloroacetamide, N,N-diallylu-chloroacetamide, N allyl N methyl-a-chloroacet' amide, N- methyl N isopropyl 0c chloroacetamide, N,N di(2 methoxyethyl) or chloroacetamide, N, N-di(2 ethoxyethyl) a chloroacetamide, N (2- ethoxyethyl) cc chloroacetamide, N n butyl-uchloroacetamide, N,N di n butyl-oc-chloroacetamide, and the like, and the corresponding a-bromoacetamides, and methyl a-chloroacetate, ethyl a-chloroacetate, isopropyl oz chloroacetate, n butyl a chloroacetate, isobutyl u chloroacetate, and the like, and the corresponding a bromoacetates.

The fungicidal and insecticidal agents of this invention are fl-arylamino cinnamoyl compounds of the general formula wherein A has the aforedescribed significance and preference, and wherein Ar and Ar are like or unlike aryl having from 6 to 10 carbon atoms such as phenyl, alkylphenyl (e.g. tolyl, xylyl, ethylphenyl, cumyl, cymenyl, butylphenyl, and the various isomeric forms thereof), and alkoxyphenyl (e.g. anisyl, dimethoxyphenyl, phenetyl, diethoxyphenyl, propoxyphenyl, butoxyphenyl, and the various isomeric forms thereof). The fl-arylamino cinnamides are fungicides while the fl-arylamino cinnamoyl compounds are insecticidally active against mosquito larvae. I The ,B-arylamino cinnamoyl compounds of this invention are prepared by initially reacting substantially equimolecular proportions of sodium hydride and a sulfonium halide of the aforedescribed formula under anhydrous conditions in the presence of tetrahydrofuran under a nitrogen atmosphere until an approximately equimolecular amount of hydrogen evolves, and thereafter adding to the reaction mass so obtained under a nitrogen atmosphere a substantially equimolecular amount of a Schiffs base of the formula ArCH=NAr' wherein Ar and Ar have the aforedescribed significance. In the reaction between the sulfonium halide and sodium hydride temperatures in the range of from about 10 C. to about 30 C. will be employed. In the reaction involving the Schiifs base any temperature can be employed which provides a fluid system (i.e. a reaction temperature above the freezing point of the system up to and including the reflux temperature of the system). Exemplary of the Schilfs base reactants are benzalaniline, N (p methoxybenzylidene)aniline, N (m methoxybenzylidene)aniline, N-'

. V 3 As illustrative of this invention but not limitative thereof is the following:

Example I To a suitable reaction vessel equipped with a thermometer and agitator 75-.1 parts by weight (substantially 1.2 moles) of dimethyl sulfide and 149.6 parts by weight (sub- 'stantially 1.0 mole) of N,N-diethyl-u-chloroacetamide. The so charged mass is heated at about 40 C. for fourteen hours, filtered and the filter cake dried under anhydrous nitrogen to give 98.8 parts by weight of dimethyl(N,N- diethylcarbamoylmethyl)-sulfoniurn chloride To a suitable reaction vessel equipped with a vent, thermometer and agitator is charged 12.0 parts by weight (substantially 0.05 mole) of dimethyl(N,N-diethylcarbamoylmethyl)-sulfonium chloride and 350 parts by weight of anhydrous tetrahydrofnran. While agitating the so charged mass under a nitrogen atmosphere there is added 2.3 parts by weight (substantially 0.05 mole) of sodium hydride in the form of a 53% by weight dispersion in mineral oil. The system is immediately connected to a gas meter to observe the evolution of hydrogen. After agitat'.

carbamoylmethyDsulfonium chloride and benzalaniline there 'is obtained fl-anilino-N,N-diallylcinnamide which melts at 90-91 C.

Example VIII Employing the procedure of Example I but replacing N,N-diethyl-u-chloroacetamide with an equimolecular amount of N-n-propyl-a-chloroacetamide there is obtained dimethyl(N n propylcarbamoylmethyl)sulfonium chloride, asolid of hygroscopic nature.

Example IX Employing the procedure of Example II but replacing V dimethyl(N,N diethylcarbamoyhnethyl)sulfonium chloing for about two hours at room temperature approxiwhich melts at 108ll0 C.

Example III Employing the procedure of Example I but replacing N,N-diethyl-u-chloroacetamide with an equimolecular amount of N,N-diethyl-a-bromoacetamide there is obtained dimethyl(N,N-diethylcarbamoylmethyl)sulfonium bromide.

Example IV Employing the procedure of Example II but replacing N-(p-methoxybenzylidene)aniline with an 'equimolecul-ar amount of N-(m,m'-dimethylbenzylidene)aniline there is obtained B-anilino-N,N-diethyl-m,m'-dimethylcinnamide.

Example V Employing the procedure of Example II but replacing N-(p-methoxybenzylidene)aniline with an equimolecular amount of benzalaniline [sometimes termed N-(benzylidene)aniline] there is obtained fi-anilino-N,N-diethylcinnamide'which melts at 9-l92 ,C.

Example VI Employing the procedure of Example I but replacing N,N-diethyl-a-chloroacetamide with an equimolecular amount of N,N-diallyl-a-chloroacetamide there is obtained dimethyl(N,N diallylcarbamoylmethyl)sulfonium chloride which melts at 120-121 C.

Example VII Employing the procedure of Example II but replacing dimethyl(N,N diethylcarbamoylmethyl)sulfonium chloride and N-(p-methoxybenzylidene)aniline, respectively, with equimolecular proportions of dimethy1(N,N-diallylride with an equimolecular amount of dimethyl(N-n-propylcarbamoylrnethyl)-sulfonium chloride there is ob tained p-anilino-N-n-propyl-p-methoxycinnamidc.

I Example X Employing the procedure of Example II but replacing dimethyl(N,N diethylcarbamoylmethyl)sulfonium chloride and N-(p-methoxybenzylidene)aniline, respectively,

with equimolecular proportions of dimethyl(N-n-propyl-.

carbamoylmethybsultonium chloride and benzalaniline there is obtained fi-anilino-N-n-propylcinnamide which melts at Ill-113 C.

Example XI Employing the procedure of Example I but replacing N,N-diethyl-u-chloroacetamide with an equimolecular amount of ethyl u-bromoacetate there is obtained dimethyl (ethoxycarbonylmethyl)sulfonium bromide [(ona)lscng o omb rsr which melts at -87 C.

Example XII Employing the procedure of Example H but replacing dimethyl( N,N diethylcarbamoylmethyl)sulfonium chloride and N-(p-methoxybenzylidene), respectively, with equimolecular proportions of dimethyl(ethoxycarbonylmethyl) sulfonium bromide and benzalaniline there is obtained ethyl p-anilinocinnamate CpH -NH o 0lH5c=oi1-iio. 3n1,

which melts at 67-68" C.

Example XIII Employing the procedure of Example I but replacing N,N-diethyl-a-chloroacetamide with an equimolecular amount of isopropyl a-chloroacetate there is obtained dimethyl(isopropoxycarbonylmethyl)sulfonium chloride.

Example XIV Employing the procedure of Example II but replacing dimethyl(N,N diethylcarbamoylmethyl)sulfonium chloride with an equimolecular amount of dimethyl(isopropoxycarbonylmethyl)-sulfonium chloride there is obtained isopropyl ir-anilino-p-methoxycinnamate.

Example XV 'To a'concen'trated aqueous solution of dimethyl(N, N- diallylcarbamoylmethyl)sulfonium chloride is added in small increments an equimolecular amount of potassium 1 iodide while agitating at room temperature. The mass is filtered and the filter cake dried under anhydrous nitrogen to give dimethyl'(N,N-diallylcarbamoylmethyl)sulfonium iodide which melts at 103-105 C.

Example XVI Employing theprocedure of Example XV but replacing dimethyl(N,N diallylcarbamoylmethyl)sulfoniurn chloride with an equimolecular amount of dimethyl(N,N 'diethylcarbamoylmethyl)sulfonium chloride there is ob-; tained dimethyl(N,N-diethylcarbamoylmethyl)sulfonium iodide. V

Example XVII Example XVIII Employing the procedure of Example I but replacing N,N diethyl cc chloroacetamide with an equimolecular amount of N allyl a chloroacetarnide there is obtained dimethyl(N allylcarbamoylmethyl)sulfonium chloride.

Example XIX Employing the procedure of Example I but replacing dimethyl sulfide with an equimolecular amount of diethyl sulfide there is obtained diethyl(N,N diethylcarbamoylmethyl)sulfonium chloride."

Example XX Employing the procedure of Example I but replacing dimethyl sulfide with an 'equimolecular amount of n-butylmethyl sulfide (ile. n-C H SCH there is obtained n-butylmethyl(N,N diethylcarbamoylmethyl)sulfonium chloride Example XXI Employing the procedure of Example I but replacing N,N diethyl cc chloroacetamide with an equimolecular amount of N methyl N isopropyl a-chloroacetamide there is obtained dimethyl(N methyl- N isopropylcarbamoylmethyl) sulfonium chloride.

Example XXII Employing the procedure of Example I but replacing N,N diethyl oz chloroacetamide with an equimolecular amount of N,N di( ethoxyethyl) a chloroacetamide there is obtained'dimethyl{N,N di(2 ethoxyethyl)carbamoylmethyl1sulfonium chloride.

Example XXIII Employing the procedure of Example II but replacing N (p methoxybenzylidene)aniline with an equimolecular amount of benzal-p-methoxy-o-toluidine there is obtained fi-(p-methoxy-o-toluidino)-N,N-diethylcinnamide.

Example XXV Employing the procedure of Example II but replacing N-(pn1ethoxybenzylidene)aniline with an equimolecular amount of N (p ethoxybenzylidene) p-toluidine there is obtained p-(p-toluidino) N,N diethyl-p-ethoxycinnamide.

Example XXVI Employing the procedure of Example II but replacing dimethyl(N,N diethylcarbamoylmethyl)sulfonium chloride with an equirnolecular amount of dimethyl(N-ally1- carbamoylmethyDsulfonium chloride there is obtained fi-anilino-N-allyl-p-methoxycinnarnide.

Example XX VII Employing the procedure of Example II but replacing dimethyl(N,N diethylcarbamoylmethyl) sulfonium chloride and N (p-methoxybenzylidenejaniline, respectively, with equimolecular proportions of dimethyl(N methyl- N isopropylcarbamoylmethyl)sulfonium chloride and benzalaniline there is obtained 18 anilino N methyh N-isopropylcinnamide.

Example XX VIII Employing the procedure of Example II but replacing dimet-hyl(N,N diethylcarbamoylmethyl)sulfonium chloride and N (p methoxybenzylidene)aniline, respectively, with equimolecular proportions of dimethyl[N,N- di(2 ethoxyethyl)carbamoylrnethylJsulfonium chloride and N (m,p dimethoxybenzylidene)aniline there is obtained ,8 anilino N,N di(2 ethoXyethyl)m,p-dimethoxycinnamide.

i I Example XXIX Employing the procedure of Example II but replacing dimethyl(N,N diethylcarbamoylmethyl)sulfonium chloride and N (p methoxybenzylidene)aniline, respectively, with equimolecular proportions of dimethyl(N,N- diallylcarbamoylmethyl)sulfonium iodide and benZal-ptert.butylaniline there is obtained 5 (p-tert.butylani1ino) N,N-diallylcinnamide.

Example XXX Employing the procedure of Example II but replacing dimethyl(N,N diethylcarbamoyl-methyl)sulfonium chloride and N (p-methoxybenzylidene)aniline, respectively, with equimolecular proportions of dirnethy1(ethoxycarbonylrnethyDsulfonium iodide and benZal-o-toluidine there is obtained ethyl fi-(o-toluidino)cinnamate.

Other sulfonium halide precursors and fi-arylamino cinnamoyl compounds which can be prepared in accordance with the procedures of this invention include dimethyl(N-methylcarbamoylmethyl) sulfonium chloride,

dimethyl(N-ethylcarbamoyhnethyl)sulfonium chloride,

dmethyl(N-isopropylcarbamoylmethyl) sulfonium chloride,

dimethyl (N-isobutylcarbamoylmethyl)sulfonium chloride,

dimethyl (N-n-but-Z-enylc arb amoylmethyl sulfonium chloride,

dimethyl [N- (Z-methoxyethyl) carbamoylmethyl1sulionium chloride, I

diethyl(N-n-pnopylcarbarnoylmethyl)sulfonium chloride,

diethyl(N,N dimethylcarbamoylmethyl)sulfonium chloride,

diethyl(N,N-diallylcarbamoylmethyl)sulfonium chloride,

diethyl (N,N-dibut-2-enylcarbamoylmethyl) sulfonium chloride,

diethyl (N,N-di-n-butylcarb amoylmethyl) sulfonium chloride,

diethyl (N-methyl-N-isopropylcarb amoylmethyl) sulfonium chloride,

methylethyl (N,N-diallylcarbamoylmethyl) sulfonium chloride,

methylethyl (N,N-dimethylcarb amoylmethyl sulfonium chloride,

diiosopropyl(N,N-diallylcarbamoylmethyl)sulfonium chloride,

di-n-butyl (N,N-diallylcarbamoylmethyl) sulfonium chloride, r, 1

dimethyl(methoxycarbonylmethyl)sulfonium chloride,

diethyl(ethoxycarbonylmethyl) sulfoniu-m chloride,

methylethyl (ethoxycarbonylmethyl)sulfonium chloride,

methylet-hyl(isopropoxycarbonylmethyl)sulfonium chloride,

diisopropyl(methoxycarbonylmethyl)sulfonium chloride,

di-n-butyl(isobutoxycarbonyhnethyl)sulfonium chloride,

and the corresponding sulfonium bromides and sulfonium iodides;

p-anilino-N-methylcinnamide,

.p-anilino-N-ethylcinnamide,

' ethyl fl-anilino-p-isopropylcinnamate,

isopropyl {i-anilinocinnamate,

isopropyl ,B-anilino-m-ethoxycinnamate, n-butyl B-anilinocinnamate, 7

methyl fi-(m-anisidinokinnamate,

ethyl B-(p-phenetidinokinnamate,

methyl B-(m,p-dimethoxyanilino) cinnamate, ethyl ,B-(p-isobutoxyanilino) cinnamate,

and the like.

The effectiveness of the compounds of this invention as fungicides is illustrated below.

Slide germination test.--By the slide germination test the concentration of the compound to be evaluated required to inhibit complete germination of spores from,7- to l-day-old cultures of Venturia inaequalz's is determined. 1.0 gram of the compound (below itemized) is dissolved in acetone to make a concentrated solution thereof and thereto is added and intimately mixed 0.1

gram of'sorbitan monolaurate polyoxyethylene derivative (a commercial water-soluble non-ionic emulsifying agent). Thereto is added and intimately mixed suificient,

Water to provide an aqueous emulsion containing 10 ppm. of the compound. To a test tube is then added four volumes of the aqueous emulsion and one volume of spore stimulant and 1 volume of spore suspension, the spore stimulant being added to insure a high and relatively stable percentage of germination in the control. Drops of the test specimen mixture and an untreated control are pipetted onto glass slides. The glass slides are then placed in moist chambers for hours incubation at 22 C. Germination counts are made by counting 100 potentially viable spores, i.e. those spores which would germinate under the normal conditions of the control. The results were as follows:

Com-pound Germination Dimethyl(N,N diallylcarbamoylmethyl) sulfonium bromide None Dimethyl(N,N diallylcarbamoylmethyl) sulfonium iodide None DimethyMhLN diallylcarbamoyhnethyl) sulfonium chloride None Dimethyl(N n-propylcarbamoylmethyl) sulfonium chloride None fl-anilino-N,Ndiethylcinnamide None p-anilino-N,N-diallylcinnamide None Control Complete In a similar evaluation against the late blight fungus Phytophthora infestans at respective concentrations of 10 p.p.m. dimethyl(N,N-diallylcarbamoylmethyl)sulfonium 8 bromide, dimethyl(N n'- propyloarbamoylmethyDsulfonium chloride and fi-anilino-N,N-diethylcinnamide, respectively, completely prevented germination of spores of said fungus.

' With respect to the soil fungus .Pythium ultimum at a concentration of 30 ppm. dimethyl(N,N-diallylcarbamoylmethyl) -sulfonium bromide and p-anilino-N,N-diethylp-methoxycinnamide, respectively, exhibited complete control of the said soil fungus. 7

As aforementioned the alkyl p-arylamino cinnamates of this invention effectively control mosquito larvae. For

example at a concentration of 10 ppm. ethyl fl-anilinov cinnamate exhibited a kill of yellow fever mosquito larvae, Aedes aegypti.

The exact concentration of the fungicidal or insecticidal 1 agents of this invention employed in combatting or controlling fungi or insects can vary considerably provided the required dosage (i.e., a toxic amount) thereof is supplied to the respective organisms or to the environment of the organisms. When the extending agent is a liquid or mixture of liquids (e.g. as in solutions, suspensions, emulsions, or aerosols) the concentration of the fungicidal or insecticidal agent employed to supply the desired dosage generally will be in the range of 0.001 to 50 percent by weight. When the extending agent is a semi-solid or solid,

the concentration of the fungicidal or insecticidal agent employed to supply the desired dosage generally will be in the range of 0.1 to 25 percent by weight. From a practical point of view, the manufacturer must supply the agriculturist with a low-cost concentrate or spray base or particulate solid base in such form that, by merely mixing with water or solid extender (e.g., powdered clay or talc) or other low-cost material available to the agriculturist at the point of use, he will have an easily prepared fungicidal or insecticidal spray or particulate solid.

In such a concentrate compositiom-the fungicidal or insecticidal agent generally will be present in a concentration of 5 to percent by weight, the residue being any one or more of the well-known fungicidal or insecticidal adjuvants, such as the various surface active agents(e.g., detergents, a soap or other emulsifying or wetting agent,

surface-active clays), solvents, diluents, carrier media, ad-

hesives, spreading agents, humectants, and the like.

In controlling or combatting fungal organisms or insects the fungicidal or insecticidal agents of this invention either per se or compositions comprising same are supplied to the fungi or insects or to their environment in a toxic amount. This can be done by dispersing the new fungicidal or insecticidal agent or fungicidal or insecticidal composition comprising same in, on or over an infested environment or in, or or over an environment the fungi or insects frequent, e.g. agricultural soil or other growth media or other media infested with the fungi or insects, or attractable to the fungi or insects for habit-ational or sustenance or propagational purposes, in any conventional fashion which permits contact betweenxthe organisms and the fungicidal or insecticidal agents of this invention. Such dispersing can be brought about by applying the fungicidal agent per se or sprays or particulate solid compositions containing same to a surface infested with the fungi or insects or attractab'le to same, as for example, the surface of agricultural soil or other media such as the above ground surface of plants by any of the conventional methods, e.g. power dusters, boom and hand sprayers, and spray dusters. Also for sub-surface applications such dispersing can be carried out by simply mixing the new fungicidal or insecticidal agent per se or fungicidal or insecticidal spray or particulate solid compositions comprising same withthe infested environment or with the environment the fungi or insects frequent, or by employinga liquid carrierfor the new fungicidal or insecticidal agent to accomplish sub-surface penetration and impregnation therein.

What is claimed is:

1.v The method of controlling Venturin inaequalis which comprises contacting same with a fungicidally toxic amount of a B-anilino-cinnamide of the formula GHHr-NH a) /R CqH;C=CH-CN wherein R and R are like lower n-alkyl.

2. The method of cont-rolling Ventzm'a inaequalis which comprises contacting same with a fungicidally toxic amount of a p-anilino-cinnamide of the formula C HrNH (I) tH=-G=cH( :-N

wherein R and R are like lower n-alkenyl.

3. The method of controlling Venturiw inaequalis which comprises contacting same with a fungicidally toxic amount of B-anilino-N,N-diethylcinnamide.

4. The method of controlling Venturia inaequalis which comprises contacting same with a fungicidally toxic amount of p-anilino-N,N-diallylcinnamide.

5. The method of controlling mosquito larvae which comprises contacting same with an insecticidally toxic amount of a p-anilino-einnamate of the formula Ar-IFH Ar-C=CHCA wherein A is lower alkoxy and wherein Ar and Ar respectively are aryl having from 6 to 10 carbon atoms sewherein Ar and Ar respectively are aryl having from 6 to 10 carbon atoms selected from the group consisting of phenyl, alkylphenyl and alkoxyphenyl, wherein R is selected from the group consisting of lower alkyl, lower alkenyl and lower alkoxyalkyl, and wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkoxyalkyl.

References Cited King: Chemicals Evaluated as Insecticides and Repellents at Orlando, Fla., Agriculture Handbook No. 69 (May 1954), pp. 116-120.

ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner. 

5. THE METHOD OF CONTROLLING MOSQUITO LARVAE WHICH COMPRISES CONTACTING SAME WITH AN INSECTICIDALLY TOXIC AMOUNT OF A B-ANILINO-CINNAMATE OF THE FORMULA
 7. THE METHOD OF CONTROLLING FUNGI WHICH COMPRISES CONTACTING SAME WITH A FUNGICIDALLY TOXIC AMOUNT OF A B-ANILINO-CINNAMIDE OF THE FORMULA 